Genome WIde Association Study of Post Traumatic Stress Disorder
PTSD Overview Post Traumatic Stress Disorder (PTSD) is a psychiatric disorder that arises from traumatic experiences. It it can become a chronic problem, however, this is dependent upon the person as well as the type of traumatic experience that was endured. Commonly seen in war veterans due to extreme violence and danger, PTSD can also be developed by people that have been mugged, raped, tortured, abused, or have been in a serious accident. As the source of PTSD is widely known to stem from these terrifying experiences, the biological causes are being studied to pinpoint why it may occur in some people and not others, or even the severity of the disorder amongst the diagnosed population. Recently a Genome-Wide Association Study was performed to identify new susceptibility loci for PTSD. Association studies have proved that the risk of PTSD development is linked to genetic variants among the population. The criteria for reliable test subjects was based on data collection from trained interviewers. Different types of traumatic experiences were assessed and possible PTSD symptoms were recorded during the interviews and integrated into a quantitative scale for analysis. Genomic Analysis A GWAS was performed by using a microarray analysis that provided 870,000 SNP's for examination. The genomic analysis included 1,578 European Americans and 2,766 African Americans in which researchers looked for common risk alleles after quality control measures were taken. To collect DNA, cells from blood or saliva and were used and genotyped by the Center for Inherited Disease Research at Yale Center for Genome Analysis. PTSD inheritability has been confirmed by previously performed twin studies, but this is the first time scientists have been able to identify genetic variants via gene association studies. Although there were multiple relevant SNP's, the most significant SNP was rs406001 on chromosome 7p12 in European Americans. It was the only SNP that exceeded "genome-wide significance" (p=3.97x10^-8). In addition to rs406001, the Tolloid-Like 1 gene (TLL1) was discovered to have a susceptibility gene locus. This GWAS analysis did not provide any conclusive evidence of association with PTSD in African Americans but did show conclusive results for European Americans. The first intron of TLL1 located at chromosome 4q32 has a high association with patients with PTSD. Mice studies have shown that TLL1 is one of four proteins that are expressed in the cerebellum and hippocampus. The hippocampus is the part of the brain that handles emotion and is a target of stress hormones. Furthermore, glucocorticoids are hormones that regulate stress response in mammals and were found to have the capability of lowering the expression of the TLL1. This GWAS study looking at TLL1, the researchers used an independent sample of 2000 European Americans which led them to confirm SNP's rs6812849 and rs7691872 within TLL1's first intron. Although this GWAS was performed using two groups of people (European American or African American), SNP's rs6812849 and rs7691872 were not associated with PTSD in African Americans. The GWAS results were further analyzed with a TaqMan genotyping array, confirming the genome-wide significance of TLL1 with regard to PTSD in European Americans. GWAS Significance This GWAS provides insight into how we might study and assess PTSD. From the deepest biological standpoint, we now know the location of genetic factors from chromosomes 7p12 and 4q32. Despite the findings of the TLL1 relationship with PTSD, PTSD is a disease that varies among the population because of factors such as the age and the type/severity of the experience. There have been other GWAS's performed on PTSD that attempted to connect a gene called RORA (Retinoid-related Orphan Receptor) with PTSD pathogenesis. Although the results were meaningful in that there is association with RORA and PTSD, this gene is primarily linked to other psychiatric diseases such as depression, ADHD, and bipolar disorder. Due to the complexity of PTSD, this particular GWAS study suggested that a much larger sample size is needed to find appropriately conclusive results to identify the neurotoxic effects RORA may have. This particular GWAS identifying TLL1 and the SNP's rs406001, rs6812849, and rs7691872 is one of the most significant studies ever performed on PTSD. Even though there was genome wide significance found within this study, it is important to understand that vast amount of genes within the human species. After all, this GWAS did show that there were inconclusive results for the African American population but conclusive results for the European American population. This study is not complete because there can always be a larger sample size and different methodical approaches towards discovery. Maybe a genetic analysis can help provide additional information to the genes associated with this disorder. References 1. Genome-wide Association Study Identifies New Susceptibility Loci for Posttraumatic Stress Disorder (PMCID: PMC3810148) 2. Genetics of Post-Traumatic Stress Disorder: Review and Recommendations for Genome-Wide Association Studies (PMCID: PMC3108177) 3. Post Traumatic Stress Disorder (PTSD) (National Institute of National Health) 4. A genome-wide association study of posttraumatic stress disorder identifies the retinoid-related orphan receptor alpha (RORA) gene as a significant risk locus (PMCID: PMC3494788)